engleski

3-Hydroxyquinuclidinium derivatives: reversible and acylating inhibitors of acetylcholinesterase

Four compounds were tested for their inhibitory effect on acetylcholinesterase (EC 3.1.1.7): 3-hydroxy-N-methylquinuclidinium N-(3-(2-iodide(I), N-[3-(3-methyl-2-hydroxyiminomethyl-1-imidazolio)-2-oxa-propyl]-3-hydroxyquinuclidinium dichloride (II)and the dimethyl-carbamates of the compounds I and II (compounds III and IV respectively). Native human erythrocytes were the enzyme source and the activity was measured in 0.1 M phosphate buffer pH = 7.4 with acetylthiocholine (ATCh) as the substrate. The enzyme/inhibitor dissociation constants were evaluated from the apparent issociation constants as function of the ATCh concentration (0.05-1.0 mM). All compounds were reversible inhibitors of AChE and the dissociation constants were between 0.2 and 0.5 mM. Compounds III and IV were also acylating AChE inhibitors. The oxime group in the compounds II and IV hydrolysed ATCh at a rate which interferred with the enzyme catalysed hydrolysis of ATCh. In order to slow down the ATCh/oxime reaction, reversible inhibition by the compounds II and IV was also measured at a low temperature.

Quinuclidinium-imidazolium compounds; Quinuclidinium carbamates; Reversible and progressive acetylcholinesterase inhibition; Reaction of acetylthiocholine with quinuclidinium carbamates

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